Neurological Phenotypes in Mouse Models of Mitochondrial Disease and Relevance to Human Neuropathology

Round 1

Reviewer 1 Report

The manuscript of Olkhova et al. provides a comprehensive overview on the mouse models in mitochondrial diseases.  The authors focus on neurological phenotypes and neuropathological features, especially on the specific neuronal subtypes and highlight, at least, the partial inability of murine models to reproduce certain features observed in humans affected with nDNA mitochondrial diseases. The review focuses on variants in nDNA that encode part of the OXPHOS system.

The introduction provides a sufficient background and an overview on the complexity and heterogeneity of mitochondrial disease and neurological phenotypes related to them, as well as on selectivity of the brains region affected. The manuscript is logically structured and focuses on the following issues: selective neuronal and glial cell types affected, and their relation to particular neurological symptoms, especially ataxia and epilepsy. The authors describe the mouse models and their phenotypes in detail, and tables as well as figure facilitate the understanding of this complex topic. Finally, authors try to provide explanation for the fact that mice model fail to recapitulate neurological phenotype.

The manuscript is well written and provides the summary of the new aspects of mice model of mitochondrial diseases. 

Comment:

In the paragraph 8 I would provide reasons for lack of the neurological phenotype in mice, such as described e.g. here https://doi.org/10.1016/j.bbagen.2020.129835

Author Response

We are extremely grateful for the reviewer's complimentary feedback and for recognising the importance of this manuscript. We revised the manuscript and inserted a sentence in paragraph 8 as suggested (lines 115-116), including the reference mentioned. We thank the reviewer for their suggestion and we think it has improved our review article by guiding the reader to another review paper, which mainly summarises the models of mtDNA disease and complexities of recapitulating the broad range of human phenotypes, should the reader wish to explore the topic further.

Reviewer 2 Report

Mitochondrial diseases are common inherited neurometabolic disorders for which there is no effective therapy in most patients. In vivo models are needed to understand disease mechanisms. This review summarizes mouse models with impairments of genes regulating mitochondrial function and discusses their neurological phenotypes and neuropathological features. The authors have provided a comprehensive analysis of the molecular and cellular basis of mitochondrial dysfunction, highlighting the complex interplay between mitochondrial DNA mutations and neuronal morphology. The authors have made an important contribution to the field of neuroscience by studying the various neurological phenotypes that occur in mouse models of mitochondrial disease. The review article is well organized and provides a clear and concise overview of current research in this area. The authors have also taken care to discuss the relevance of their findings to human neuropathology, which adds to the importance of this review. They have done an excellent job of summarizing the key findings. The article is recommended for publication without changes.

Author Response

We thank the reviewer for their complimentary feedback, especially for highlighting the crucial aspect of this paper comparing the mouse model neuropathology to human post-mortem neuropathological studies.